P1364: PHARMACOKINETIC PROFILE OF VARNIMCABTAGENE AUTOLEUCEL (IMN-003A), FIRST-IN-INDIA INDUSTRY CD19-DIRECTED CAR-T CELL THERAPY FOR PATIENTS WITH RELAPSED/ REFRACTORY B CELL MALIGNANCIES (IMAGINE STUDY)
Authors: Pankaj Malhotra, Sunil Bhat, Sharat Damodar, Raja Thirumalairaj, Revathy Raj, Pooja Mallya, Akshatha Nayak, Ravi Joshi, Sudarshan Chougule, Deepak Mb, Sudeshna Dhar, Anne Roshan Joseph, Arun Kumar Mg, Jeetendra Kumar, Melina Soares, Sunil Yadav, Pallavi Arasu, Sri Ramulu Elluru, Mohammed Manzoor Akheel, Rahul Nahar, Anil Kamat
Journal: HemaSphere (2023)

Topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research Background: Varnimcabtagene autoleucel (IMN-003A) is an autologous CD19 directed CAR-T cell product with a 4-1BB co-stimulatory domain and A3B1 binder, a non-FMC63 murine single chain variable fragment, manufactured in India and tested in the IMAGINE study (CTRI/2022/03/041162), a phase-2 clinical trial for patients (pts) with relapsed/ refractory B cell malignancies. A fractionated infusion of 1 x 106 CAR+ cells (IMN-003A)/kg for B-ALL cohort and 5 x 106 CAR+ cells (IMN-003A)/kg for B-NHL cohort was administered over 3 days as 10%, 30% and 60% fractions after Flu-Cy lymphodepletion regimen. Safety and efficacy results are submitted in a separate abstract. Here we present the IMN-003A pharmacokinetic data and correlation with disease response. Aims: Study the pharmacokinetic profile of varnimcabtagene autoleucel (IMN-003A) and correlation with disease response. Methods: Peripheral blood (PB) samples were obtained after consent at screening and as per patient schedule after infusion. Persistence of IMN-003A was evaluated in PB after infusion by ddPCR. Safety and efficacy data were collected for analysis. Bone marrow minimal residual disease (MRD) was performed by flowcytometry (FC) at 10-4 sensitivity at screening, D+28 and D+90 for efficacy. IMN-003A was manufactured using cGMP compliant closed system (CliniMACS Prodigy). The manufacturing data was analyzed, including % CAR transduction in the final product (FP) by FC. Apheresis, FP, and PB samples were analyzed for T-cell subpopulations and surface markers by FC. Results: Twenty-one pts underwent apheresis and selected T cells were transduced to achieve the FP with a median manufacturing time of 14d (range 10-27) with 100% success. Two pts underwent second apheresis. The mean % transduction of IMN-003A on autologous T cells was 33.59% (range 8.50 - 58.35) with median transgene copies/ genome of 2.27 (range 0.76 – 4.16). The mean CD4/CD8 ratio at apheresis and final product was 0.81 and 1.03 respectively. The mean proportion of CD4 and CD8 positive naïve cells (CCR7+ RA+) was above 35% in the final product (Figure 1A). Median Product Doubling time and Apheresis to Infusion time was 1.04d (range 0.83 – 4.20) and 22d (range 16 - 95) respectively. Post IMN-003A infusion, there was a trend towards reversal of CD4/CD8 ratio. IMN-003A CAR-T cells showed maximum PB expansion (Tmax) at median 10d (range 7 – 21) with median Cmax 135,693 CAR copies/ μg gDNA (range 24,624 – 413,968). CAR-T cell persistence in PB was 94% at D+28 and 36% at D+90 (range 21 - NR). All pts had B-cell aplasia concurring with CAR-T expansion (Figure 1B); median not reached (range 42 - NR), with no apparent association with response at D+28 and D+90. Hypogammaglobulinemia was noted in 14 of 19 evaluable pts and 9 pts received IVIg. Of evaluable patients, CD4+ T-cell count recovery (>200/μL) was seen at median of 12 days (range 2 - 42) after infusion. Overall response rate (ORR) was 88.2% at D+28 and 72.7% at D+90. Two pts relapsed by D+90. Of MRD-evaluable pts, response was 100% at day+28 (n=7) and 83.3% at D+90 (n=6). Updated results will be presented at the meeting. Summary/Conclusion: In this industry-led first-in-India phase-2 study, IMN-003A production in a cGMP closed system was 100% successful and rapid. The peak of CAR-T expansion occurs at median 10d of infusion. Responses at D+90 are sustained and deep.Keywords: Acute lymphoblastic leukemia, Non-Hodgkin’s lymphoma, CAR-T, Pharmacokinetic